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Volume 38 Issue 3
June 2023
    Citation: Jingliang Chen, Yaozu He, Huolin Zhong, Fengyu Hu, Yonghong Li, Yeyang Zhang, Xia Zhang, Weiyin Lin, Quanmin Li, Feilong Xu, Shaozhen Chen, Hui Zhang, Weiping Cai, Linghua Li. Transcriptome analysis of CD4+ T cells from HIV-infected individuals receiving ART with LLV revealed novel transcription factors regulating HIV-1 promoter activity .VIROLOGICA SINICA, 2023, 38(3) : 398-408.  http://dx.doi.org/10.1016/j.virs.2023.03.001
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    Transcriptome analysis of CD4+ T cells from HIV-infected individuals receiving ART with LLV revealed novel transcription factors regulating HIV-1 promoter activity

    • a. Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, 510060, China;

    • b. Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China;

    • c. Guangzhou Laboratory, Bio-Island, Guangzhou, 510320, China

    • Some HIV-infected individuals receiving ART develop low-level viremia (LLV), with a plasma viral load of 50–1000 copies/mL. Persistent low-level viremia is associated with subsequent virologic failure. The peripheral blood CD4+ T cell pool is a source of LLV. However, the intrinsic characteristics of CD4+ T cells in LLV which may contribute to low-level viremia are largely unknown. We analyzed the transcriptome profiling of peripheral blood CD4+ T cells from healthy controls (HC) and HIV-infected patients receiving ART with either virologic suppression (VS) or LLV. To identify pathways potentially responding to increasing viral loads from HC to VS and to LLV, KEGG pathways of differentially expressed genes (DEGs) were acquired by comparing VS with HC (VS-HC group) and LLV with VS (LLV-VS group), and overlapped pathways were analyzed. Characterization of DEGs in key overlapping pathways showed that CD4+ T cells in LLV expressed higher levels of Th1 signature transcription factors (TBX21), toll-like receptors (TLR-4, -6, -7 and -8), anti-HIV entry chemokines (CCL3 and CCL4), and anti-IL-1β factors (ILRN and IL1R2) compared to VS. Our results also indicated activation of the NF-κB and TNF signaling pathways that could promote HIV-1 transcription. Finally, we evaluated the effects of 4 and 17 transcription factors that were upregulated in the VS-HC and LLV-VS groups, respectively, on HIV-1 promoter activity. Functional studies revealed that CXXC5 significantly increased, while SOX5 markedly suppressed HIV-1 transcription. In summary, we found that CD4+ T cells in LLV displayed a distinct mRNA profiling compared to that in VS, which promoted HIV-1 replication and reactivation of viral latency and may eventually contribute to virologic failure in patients with persistent LLV. CXXC5 and SOX5 may serve as targets for the development of latency-reversing agents.
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      Transcriptome analysis of CD4+ T cells from HIV-infected individuals receiving ART with LLV revealed novel transcription factors regulating HIV-1 promoter activity

        Corresponding author: Hui Zhang, zhangh92@mail.sysu.edu.cn
        Corresponding author: Weiping Cai, gz8hcwp@126.com
        Corresponding author: Linghua Li, llheliza@126.com
      • a. Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, 510060, China;
      • b. Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China;
      • c. Guangzhou Laboratory, Bio-Island, Guangzhou, 510320, China
      • Received Date: 29 September 2022
      • Accepted Date: 06 March 2023

      Abstract: Some HIV-infected individuals receiving ART develop low-level viremia (LLV), with a plasma viral load of 50–1000 copies/mL. Persistent low-level viremia is associated with subsequent virologic failure. The peripheral blood CD4+ T cell pool is a source of LLV. However, the intrinsic characteristics of CD4+ T cells in LLV which may contribute to low-level viremia are largely unknown. We analyzed the transcriptome profiling of peripheral blood CD4+ T cells from healthy controls (HC) and HIV-infected patients receiving ART with either virologic suppression (VS) or LLV. To identify pathways potentially responding to increasing viral loads from HC to VS and to LLV, KEGG pathways of differentially expressed genes (DEGs) were acquired by comparing VS with HC (VS-HC group) and LLV with VS (LLV-VS group), and overlapped pathways were analyzed. Characterization of DEGs in key overlapping pathways showed that CD4+ T cells in LLV expressed higher levels of Th1 signature transcription factors (TBX21), toll-like receptors (TLR-4, -6, -7 and -8), anti-HIV entry chemokines (CCL3 and CCL4), and anti-IL-1β factors (ILRN and IL1R2) compared to VS. Our results also indicated activation of the NF-κB and TNF signaling pathways that could promote HIV-1 transcription. Finally, we evaluated the effects of 4 and 17 transcription factors that were upregulated in the VS-HC and LLV-VS groups, respectively, on HIV-1 promoter activity. Functional studies revealed that CXXC5 significantly increased, while SOX5 markedly suppressed HIV-1 transcription. In summary, we found that CD4+ T cells in LLV displayed a distinct mRNA profiling compared to that in VS, which promoted HIV-1 replication and reactivation of viral latency and may eventually contribute to virologic failure in patients with persistent LLV. CXXC5 and SOX5 may serve as targets for the development of latency-reversing agents.

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